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Rac GTPases act as molecular switch in various morphogenic events. However, the regulation of their activities during the development of multicellular organisms is not well understood. Caenorhabditis elegans rac genes ced-10 and mig-2 have been shown to act redundantly to control P cell migration and the axon outgrowth of D type motoneurons. We showed that ced-10 and mig-2 also control amphid axon outgrowth and amphid dendrite fasciculation in a redundant fashion. Our biochemical and genetic data indicate that unc-73, which encodes a protein related to Trio-like guanine nucleotide exchange factor, acts as a direct activator of ced-10 and mig-2 during P cell migration and axon outgrowth of D type motoneurons and amphid sensory neurons. Furthermore, rac regulators ced-2/crkII and ced-5/dock180 function genetically upstream of ced-10 and mig-2 during axon outgrowth of D type motoneurons and act upstream of mig-2 but not ced-10 during P cell migration. However, neither ced-2/crkII nor ced-5/dock180 is involved in amphid axon outgrowth. Therefore, distinct rac regulators control ced-10 and mig-2 differentially in various cellular processes.

SummarySynaptic activity regulates the postsynaptic accumulation of AMPA receptors over timescales ranging from minutes to days. Indeed, the regulated trafficking and mobility of GluR1 AMPA receptors underlies many forms of synaptic potentiation at glutamatergic synapses throughout the brain. However, the basis for synapse-specific accumulation of GluR1 is unknown. Here we report that synaptic activity locally immobilizes GluR1 AMPA receptors at individual synapses. Using single-molecule tracking together with the silencing of individual presynaptic boutons, we demonstrate that local synaptic activity reduces diffusional exchange of GluR1 between synaptic and extraynaptic domains, resulting in postsynaptic accumulation of GluR1. At neighboring inactive synapses, GluR1 is highly mobile with individual receptors frequently escaping the synapse. Within the synapse, spontaneous activity confines the diffusional movement of GluR1 to restricted subregions of the postsynaptic membrane. Thus, local activity restricts GluR1 mobility on a submicron scale, defining an input-specific mechanism for regulating AMPA receptor composition and abundance.

Several case reports and retrospective studies have indicated that carbapenems decrease the serum concentration of valproic acid (VPA), thus decreasing its therapeutic activity. This study evaluates a potential drug interaction between VPA and carbapenems in a regional hospital. This retrospective observational study was performed over a 14-month period from January 2010 to February 2011. Patients concurrently receiving VPA and carbapenems who had at least two serially measured concentrations of serum VPA prior to, during, or after this combined treatment were included. Patients whose serum samples for VPA were drawn within 2 hours after VPA administration who had severe liver impairment or who received other drugs that could potentially interact with VPA were excluded from the study. The serum levels and therapeutic activities of VPA during coadministration of carbapenems were recorded and evaluated. Nine VPA-treated patients were identified who concomitantly received meropenem (n = 5), ertapenem (n = 3), or imipenem (n = 1). Mean serum VPA trough levels during combined treatment decreased by 76.3% (from 55.6 ± 22.9 μg/mL to 13.2 ± 6.1 μg/mL) from values before carbapenem treatment. However, only one patient experienced seizures after a combination of VPA and carbapenems. The coadministration of VPA and carbapenems resulted in decreased trough concentrations of VPA. Clinicians should be aware of this potential interaction and closely monitor serum VPA levels and possible failure to control seizures with the concomitant use of carbapenems.

Background An association between chronic obstructive pulmonary disease (COPD) and tuberculosis (TB) has been described, mainly due to smoking and corticosteroid use. Whether inhaled corticosteroid (ICS) therapy is associated with an increased risk of TB remains unclear. Methods We selected COPD cases by using six diagnostic scenarios and control subjects from a nationwide health insurance database, and applied time-dependent Cox regression analysis to identify the risk factors for TB. Results Among 1,000,000 beneficiaries, 23,594 COPD cases and 47,188 non-COPD control subjects were selected. Cox regression analysis revealed that age, male gender, diabetes mellitus, end-stage renal disease, and cirrhosis, as well as COPD (hazard ratio = 2.468 [2.205–2.762]) were independent risk factors for TB. Among the COPD cases, those who developed TB received more oral corticosteroids and oral β-agonists. Time-dependent Cox regression analysis revealed that age, male gender, diabetes mellitus, low income, oral corticosteroid dose, and oral β-agonist dose, but not ICS dose, were independent risk factors for TB. The identified risk factors and their hazard ratios were similar among the COPD cases selected using different scenarios. Conclusion Keeping a high suspicion and regularly monitoring for the development of pulmonary TB in COPD patients are necessary, especially for those receiving higher doses of oral corticosteroids and other COPD medications. Although ICS therapy has been shown to predispose COPD patients to pneumonia in large randomized clinical trials, it does not increase the risk of TB in real world practice.